In the Search of the Magic Bullet … Olav A. Gressner  Gastroenterology  Volume 139, Issue 5, Pages 1453-1457 (November 2010) DOI: 10.1053/j.gastro.2010.09.025 Copyright © 2010 AGA Institute Terms and Conditions

Figure 1 Schematic overview of proposed hepatoprotective molecular signaling pathways triggered by coffee and the ingredients therein. (I) Caffeine mediated antagonism of TGF-β signaling. Caffeine leads to an elevation of intracellular cyclic adenosine monophosphate concentrations resulting in enhanced ubiquitination/proteasomal degradation of the TGF-β effector Smad2 by the ubiquitin–ligase Smurf2, which displays high sensitivity toward this particular Smad as well as to the TGF-β type I receptor complex, to which Smad3 is allosterically bound upon activation of the receptor by its cytokine. (II) Coffee components stimulate Nrf2/ARE-regulated signal transduction. Caffeine phosphorylates Nrf2 via the MAP-kinase pathway, and kahweol and cafestol initiate thiol modification of cysteine residues in Keap1, thereby disrupting the cytoplasmic Keap1/Nrf2 complex, which results in a release of Nrf2 and in its translocation to the nucleus where it transcriptionally activates ARE-dependent genes, including several phase II xenobiotic metabolizing enzymes such as UDP-glucuronosyltransferase (UGT), glutathione S-transferase (GST), and others. In this issue of Gastroenterology, Kalthoff et al show that the induction of UGT 1A by Nrf2 in the presence of various coffee preparations is not exclusively dependent on caffeine or kahweol and cafestol, thereby triggering a new search for yet undiscovered Nrf2/ARE activating substances in coffee. Gastroenterology 2010 139, 1453-1457DOI: (10.1053/j.gastro.2010.09.025) Copyright © 2010 AGA Institute Terms and Conditions